Understanding Delayed Graft Function to Improve Organ Utilization and Patient Outcomes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Delayed graft function (DGF) is a common complication after kidney transplant. Despite extensive literature on the topic, the extant definition of DGF has not been conducive to advancing the scientific understanding of the influences and mechanisms contributing to its onset, duration, resolution, or long-term prognostic implications. In 2022, the National Kidney Foundation sponsored a multidisciplinary scientific workshop to comprehensively review the current state of knowledge about the diagnosis, therapy, and management of DGF and conducted a survey of relevant stakeholders on topics of clinical and regulatory interest. In this Special Report, we propose and defend a novel taxonomy for the clinical and research definitions of DGF, address key regulatory and clinical practice issues surrounding DGF, review the current state of therapies to reduce and/or attenuate DGF, offer considerations for clinical practice related to the outpatient management of DGF, and outline a prospective research and policy agenda.

Delayed graft function post renal transplantation: a review on animal models and therapeutics.

The incidence of end-stage renal disease (ESRD) has been increasing worldwide. Its treatment involves renal replacement therapy, either by dialyses or renal transplantation from a living or deceased donor. Although the initial mortality rates for patients on dialysis are comparable with kidney transplant recipients, the quality of life and long-term prognosis are greatly improved in transplanted patients. However, there is a large gap between availability and need for donor kidneys. This has led to the increase in the use of expanded kidney donor criteria. Allograft dysfunction immediately after transplant sets it up for many complications, such as acute rejection and shorter allograft survival. Delayed graft function (DGF) is one of the immediate posttransplant insults to the kidney allograft, which is increasing in prevalence due to efforts to maximize the available donor pool for kidneys and use of expanded kidney donor criteria. In this review, we discuss the risk factors for DGF, its implications for long-term allograft survival, animal models of DGF, and the therapeutic options currently under evaluation for prevention and management of DGF.

Deceased Donor Renal Transplantation: 6 Year Experience from a Tertiary Care Center in North India.

The incident of End stage renal disease (ESRD) is rising rapidly worldwide. Renal transplant is the best modality of treatment, offering a better quality of life and mortality benefit, as compared with long-term dialysis. Very few patients have a live renal transplant donor, for rest, a decreased donor renal transplant is the only alternative. Deceased donor renal transplantation (DDRT) programs are only available at few government centers of India, constituting less than 5% of the total renal transplants. MATERIAL: The patients who had undergone DDRT at our center from February 2015 to February 2021 were registered in the study. The following data were recorded for all patients; age, sex, duration of ESRD, cold ischemia time, type of induction, nadir and follow -up creatinine, hemoglobin, urinary protein and complications. All recipients were followed up and investigated in the outpatient department on a regular basis as per the standard guidelines till death or graft loss, whichever is earlier. Post transplant renal allograft function was measured using serum creatinine and other parameters. OBSERVATION: During the study period 51 DDRTs were done. There were 40 male and 11 female patients. The mean age was 39.9 ± 9.8 years. The most common cause of ESRD in recipients was chronic glomerulonephritis (CGN) in 92.1 % (47). Amongst the patients, 41 (80.3%) survived, while 10 (19.6%) died post-transplant. Out of ten, 6 recipients died due to early sepsis (<3 months) and 4 died due to late sepsis (>3 months). Acute rejection was present in 17.6 % of patients. Mean post- transplant creatinine in recipients with functioning graft at discharge was 1.54 mg/dl. Graft failure was present in 7 patients out of which 2 were alive at the time of writing this paper and were on maintenance dialysis. Two patients died with a functioning graft. Delayed graft function (DGF) was seen in 13.7% (n=7) of recipients. The causes of DGF in our study included transplant renal artery thrombosis (n=2), Antibody-Mediated Rejection (n=3), mixed rejection (n=1) and Acute cellular rejection (n=1). Among those who had DGF, graft loss was seen in 57.2% (n=4). CONCLUSION: In our study, the patient survival and graft survival have been better as compared to previous studies and also the number of recipients with delayed graft function have been low. Deceased donor renal transplantation is a practical treatment modality which can drastically improve longevity and quality of life.

A prediction model of delayed graft function in deceased donor for renal transplant: a multi-center study from China.

BACKGROUND: Kidneys obtained from deceased donors increase the incidence of delayed graft function (DGF) after renal transplantation. Here we investigated the influence of the risk factors of donors with DGF, and developed a donor risk scoring system for DGF prediction. METHODS: This retrospective study was conducted in 1807 deceased kidney donors and 3599 recipients who received donor kidneys via transplants in 29 centers in China. We quantified DGF associations with donor clinical characteristics. A donor risk scoring system was developed and validated using an independent sample set. RESULTS: The incidence of DGF from donors was 19.0%. Six of the donor characteristics analyzed, i.e., age, cause of death, history of hypertension, terminal serum creatinine, persistence of hypotension, and cardiopulmonary resuscitation (CPR) time were risk factors for DGF. A 49-point scoring system of donor risk was established for DGF prediction and exhibited a superior degree of discrimination. External validation of DGF prediction revealed area under the receiver-operating characteristic (AUC) curves of 0.7552. CONCLUSIONS: Our study determined the deceased donor risk factors related to DGF after renal transplantation pertinent to the Chinese cohort. The scoring system developed here had superior diagnostic significance and consistency and can be used by clinicians to make evidence-based decisions on the quality of kidneys from deceased donors and guide renal transplantation therapy.

The New Anterior Less Invasive Crescentic Incision for Living Donor Nephrectomy.

OBJECTIVES: Living-donor nephrectomy is a devoted procedure performed in a healthy individual; for these procedures, it is essential to complete the surgery with the lowest possible risk and morbidity and allow donors to regain their normal daily activity. To minimize anatomic and physiologic damage, we modified a surgical technique. Here, we report our experiences with the new anterior less invasive crescentic donor nephrectomy technique. MATERIALS AND METHODS: We retrospectively evaluated 728 donor nephrectomy patients who had the new anterior less invasive cresentic incision (n = 224), the classic open (n = 431), or the laparoscopic living-donor nephrectomy (n = 73) procedures. Demographic characteristics, preoperative and postoperative parameters, acute renal graft dysfunction, and firstyear graft and patient survival rates were compared between groups. RESULTS: During the operation, the new cresentic incision living-donor nephrectomy allowed a safe and comfortable position for the patient and the anesthesiologist. Also, it procures safe access especially for grefts with multiple vessels. Patients had lower pain scores (P = .010), shorter hospital stays (2.25 vs 3.49 days) than those who received the classic open living-donor nephrectomy. Patients who received laparoscopic living-donor nephrectomy had significantly longer mean operation time (P = .016) and warm ischemia time (P ≤ .001) than those who had the new cresentic incision technique. All groups showed similar rates of first-year survival and delayed graft dysfunction. CONCLUSIONS: The new anterior less invasive cresentic incision open-donor nephrectomy approach is a safe, comfortable, effective, and less invasive modification of the living donor nephrectomy. Also, it procures safe access for grefts with multiple vessels.

Risk for Delayed Graft Function in Deceased Donor Renal Transplant Patients: A Single-Center Experience From North India.

OBJECTIVES: Delayed graft function (DGF) in renal allograft transplantation refers to the need for dialysis in the first week after renal transplantation. This study analyzed the causes of DGF in deceased donor transplantation. METHODS: Data from January 2018 to July 2019 was reviewed with regard to donor and recipient characteristics such as demographics, biochemical parameters, organ dysfunction, and preterminal management. The recipients were divided into 2 groups: group I: patients without DGF and group II: patients with DGF. RESULTS: Kidneys were retrieved from 49 deceased donors (male:female = 41:8) and transplanted to 95 recipients (male:female = 60:35). Mean age of the donors and recipients was 35.34 ± 18.2 and 40.72 ± 13.30 years, respectively. The most common cause of brain death was central nervous system trauma (45 out of 49, 91%). In total, 20/95 (21%) recipients had DGF. Twelve recipients had received kidneys from donors who had circulatory arrest. Two patients were re-explored on postoperative day 1 for bleeding from renal artery anastomosis. The mean age in group I and group II was 28.65 ± 10.2 and 37.38 ± 12.28 years, respectively. The mean cold ischemia time in group I and group II was 398.73 ± 187.19 and 333.24 ± 115.49 minutes, respectively. The mean hospital stay of donor before donation in group I and group II was 4.34 ± 1.27 and 6 ± 2.95 days, respectively. The terminal donor creatinine in group I and group II was 0.88 ± 0.47 and 2.33 ± 1.73 mg/dL, respectively. CONCLUSION: DGF in deceased donor transplantation may be attributed to donation after circulatory death, prolonged donor hospital stay, high donor leukocyte count, and high terminal creatinine.

Thymoglobulin vs. ATG-Fresenius as Induction Therapy in Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

Background: Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation. Materials and Methods: We performed a Bayesian network meta-analysis to compare THG with ATG-F by pooling direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) values were used to compare the superiority of one method over the other. Results: A total of 27 randomized controlled trials (RCT) were eligible for the network meta-analysis. Efficacy endpoints, as well as safety indicators, were statistically comparable. For efficacy endpoints, THG seemed inferior to ATG-F in preventing delayed graft function [odds ratio (OR): 1.27; SUCRA: 78% vs. 58%], patient deaths (OR: 2.78; SUCRA: 83% vs. 34%), and graft loss (OR: 1.40; SUCRA: 83% vs. 59%), but superior to ATG-F in biopsy-proven acute rejection (BPAR; OR: 0.59; SUCRA: 78% vs. 39%) and steroid-resistant BPAR prevention (OR: 0.61; SUCRA: 76% vs. 49%) within the first year. For safety endpoints, THG was associated with higher risk of infection (OR: 1.49, SUCRA: 79% vs. 54%), cytomegalovirus infection (OR: 1.04; SUCRA: 40% vs. 37%), de novo diabetes (OR: 1.10; SUCRA: 90% vs. 30%), and malignancy (OR: 8.40; SUCRA: 89% vs. 6%) compared to ATG-F. A subgroup analysis of patients at high risk for immunologic complications revealed similar results, but THG performed better for graft loss (OR: 0.82; SUCRA: 68% vs. 54%). Conclusion: ATG-F seemed to be more effective than THG in improving the short-term kidney transplantation outcomes. Prospective head-to-head comparison of THG and ATG-F with larger sample sizes and longer follow-up is still required.

Deceased donor kidney transplant complicated by spontaneous rupture of native kidney in a HIV patient.

Spontaneous native kidney rupture (SNKR) is a rare occurrence, commonly associated with underlying renal tumors or acquired renal cystic disease in both the kidney transplant (KT) and non-KT populations. Herein, we present a 65-year-old African American man who experienced a non-malignant SNKR 6 days after a deceased donor KT and underwent emergent native nephrectomy. The patient's hospital course was complicated by thrombocytopenia and refractory hypertension. He experienced delayed graft function and was maintained on hemodialysis until post-operative day 30. This case demonstrates an unusual presentation of SNKR in the immediate post-KT setting and illustrates the clinical decision-making algorithm.

Limited clinical value of two consecutive post-transplant renal scintigraphy procedures.

OBJECTIVES: Duration of delayed graft function (DGF) and length of hospital stay (LOS) are outcomes of interest in an era that warrants increased efficacy of transplant care whereas renal allografts originate increasingly from marginal donors. While earlier studies investigate the predictive capability of a single renal scintigraphy, this study focuses on the value for both DGF duration and LOS of consecutively performed scintigraphies. METHODS: From 2011 to 2014, renal transplant recipients referred for a Tc-99m MAG3 renal scintigraphy were included in a single-center retrospective study. Primary endpoints were DGF duration and LOS. Both the first (≤ 3 days) and second scintigraphies (3-7 days after transplantation) were analyzed using a 4-grade qualitative scale and quantitative indices (TFS, cTER, MUC10, average upslope). RESULTS: We evaluated 200 first and 108 (54%) consecutively performed scintigraphies. The Kaplan-Meier curves for DGF duration and qualitative grading of the first and second scintigraphy showed significant differences between the grades (p < 0.01). The Kaplan-Meier curve for the delta grades between these procedures (lower, equal, or higher grade) did not show significant differences (p = 0.18). Multivariate analysis showed a significant association between the qualitative grades, from the first and second scintigraphy, and DGF duration, HR 1.8 (1.4-2.2, p < 0.01) and 2.8 (1.8-4.3, p < 0.01), respectively. CONCLUSIONS: Qualitative grades of single renal scintigraphies, performed within 7 days after transplantation, can be used to make a reliable image-guided decision on the need for dialysis and to predict LOS. A consecutive renal scintigraphy, however, did not show an additional value in the assessment of DGF. KEY POINTS: • Post-transplant renal scintigraphy procedures provide information to predict delayed graft function duration and length of hospital stay. • Performing two consecutive renal scintigraphy procedures within 1 week after transplantation does not strengthen the prediction of delayed graft function duration and length of hospital stay. • Single renal scintigraphy procedures can be used to provide clinicians and patients with a reliable indication of the need for dialysis after transplantation and the expected duration of hospitalization.

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report.

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m2). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.

Acute Kidney Injury in Kidney Transplants: New Insights.

Delayed allograft function (DGF) is defined as dialysis treatment in the kidney transplant recipient in the first week following transplantation. With the demand for kidney transplants growing and the supply limited, as well as implementation of a national allocation scheme for deceased donor kidneys, rates of DGF remain high, on average, 30% for recipients of deceased donor kidneys. DGF is associated with inferior allograft outcomes, and there are no FDA-approved therapies to mitigate this disorder. There is renewed interest in this therapeutic arena, and there are several recent clinical trials that have considered interventions within the recipient to reduce injury. A critical issue is that of trial design and end points as well as translating from acute kidney injury (AKI) trials in cardiac bypass to the more complicated kidney transplant scenario. DGF is a significant clinical outcome after kidney transplantation without known approved therapy beyond clinical support. This mini-review highlights our presentation at the 24th International Conference on Advances in Critical Care Nephrology and UAB/UCSD O'Brien Center AKI Pre-Meeting.

Oxalate deposition in renal allograft biopsies within 3 months after transplantation is associated with allograft dysfunction.

BACKGROUND: Calcium oxalate (CaOx) deposition in the kidney may lead to loss of native renal function but little is known about the prevalence and role of CaOx deposition in transplanted kidneys. METHODS: In patients transplanted in 2014 and 2015, all for-cause renal allograft biopsies obtained within 3 months post-transplantation were retrospectively investigated for CaOx deposition. Additionally, all preimplantation renal biopsies obtained in 2000 and 2001 were studied. RESULTS: In 2014 and 2015, 388 patients were transplanted, of whom 149 had at least one for-cause renal biopsy. Twenty-six (17%) patients had CaOx deposition. In the population with CaOx deposition: Patients had significantly more often been treated with dialysis before transplantation (89 vs. 64%; p = 0.011); delayed graft function occurred more frequently (42 vs. 23%; p = 0.038); and the eGFR at the time of first biopsy was significantly worse (21 vs. 29 ml/min/1.73m2; p = 0.037). In a multivariate logistic regression analysis, eGFR at the time of first biopsy (OR 0.958, 95%-Cl: 0.924-0.993, p = 0.019), dialysis before transplantation (OR 4.868, 95%-Cl: 1.128-21.003, p = 0.034) and the time of first biopsy after transplantation (OR 1.037, 95%-Cl: 1.013-1.062, p = 0.002) were independently associated with CaOx deposition. Graft survival censored for death was significantly worse in patients with CaOx deposition (p = 0.018). In only 1 of 106 preimplantation biopsies CaOx deposition was found (0.94%). CONCLUSION: CaOx deposition appears to be primarily recipient-derived and is frequently observed in for-cause renal allograft biopsies obtained within 3 months post-transplantation. It is associated with inferior renal function at the time of biopsy and worse graft survival.

Outcomes and challenges of a kidney transplant programme at Groote Schuur Hospital, Cape Town: A South African perspective.

INTRODUCTION: Access to dialysis and transplantation in the developing world remains limited. Therefore, optimising renal allograft survival is essential. This study aimed to evaluate clinical outcomes and identify poor prognostic factors in the renal transplant programme at Groote Schuur Hospital [GSH], Cape Town. . METHOD: Data were collected on all patients who underwent a kidney transplant at GSH from 1st July 2010 to the 30 June 2015. Analyses were performed to assess baseline characteristics, graft and patient survival, as well as predictors of poor outcome. . RESULTS: 198 patients were transplanted. The mean age was 38 +/- 10.5 years, 127 (64.1%) were male, and 86 (43.4%) were of African ethnicity. Deceased donor organs were used for 130 (66.7%) patients and living donors for 65 (33.3%). There were > 5 HLA mismatches in 58.9% of transplants. Sepsis was the commonest cause of death and delayed graft function [DGF] occurred in 41 (21.4%) recipients. Patient survival was 90.4% at 1 year and 83.1% at 5 years. Graft survival was 89.4% at 1 year and 80.0% at 5 years. DGF (HR 2.83 (1.12-7.19), p value = 0.028) and recipient age > 40 years (HR 3.12 (1.26-7.77), p value = 0.014) were predictors of death. CONCLUSION: Despite the high infectious burden, stratified immunosuppression and limited tissue typing this study reports encouraging results from a resource constrained transplant programme in South Africa. Renal transplantation is critical to improve access to treatment of end stage kidney disease where access to dialysis is limited.

Life-saving vascular access after combined liver and kidney transplantation: A challenging access to the right atrium.

Exhaustion of vascular accesses is a major complication in patients undergoing hemodialysis, especially in pediatric setting. We report the case of a boy treated for loss of hemodialysis access after a combined liver-kidney transplantation and transient renal dysfunction. An interventional dilatation of calcific superior vena cava allowed to insert a stable central venous line for dialysis until full graft recovery. Careful management of central lines allows to spare the main vessels and reduces the need for unusual accesses.

Prolonged Delayed Graft Function Due to an Extensive Renal Graft Subcapsular Hematoma: Is Conservative Management Justified?

A 62-year-old male patient with diabetes underwent deceased-donor kidney transplant at our transplant unit. At reperfusion, a small and clinically not significant subcapsular hematoma was noted. The patient's postoperative course was characterized by delayed graft function since the beginning but was further complicated on postoperative day 6 by evidence (shown at daily Doppler ultrasonography) of a wide increase of the hematoma. The hematoma, which was just visible before, was now leading to graft compression because it covered up to two-thirds of the cortical surface. The patient showed no hemo-dynamic instability and showed no significant drop in hemoglobin values. Capsulotomy was not performed because it was deemed too risky. The patient was given strict follow-up with Doppler ultrasonography and high-resolution imaging techniques (magnetic resonance imaging and computed tomography scan). In the following days, spontaneous resolution of the hematoma and progressive improvement of Doppler findings were observed, which preceded full recovery of graft function. Conservative management, in hemodynamically stable patients, seems to be a valid approach of this condition. By avoiding surgery or other interventional procedures, a conservative approach allows reduced risk of further complications. Strict monitoring with Doppler ultrasonography is a valid tool for follow-up, along with high-resolution imaging techniques such as magnetic resonance imaging and computed tomography to confirm diagnosis.

Comparison of graft and patient outcomes following kidney transplantation in extended hour and conventional haemodialysis patients.

AIM: Differences in early graft function between kidney transplant recipients previously managed with either haemodialysis (HD) or peritoneal dialysis are well described. However, only two single-centre studies have compared graft and patient outcomes between extended hour and conventional HD patients, with conflicting results. METHODS: This study compared the outcomes of all extended hour (≥24 h/week) and conventional HD patients transplanted in Australia and New Zealand between 2000 and 2014. The primary outcome was delayed graft function (DGF), defined in an ordinal manner as either a spontaneous fall in serum creatinine of less than 10% within 24 h, or the need for dialysis within 72 h following transplantation. Secondary outcomes included the requirement for dialysis within 72 h post-transplant, acute rejection, estimated glomerular filtration rate at 12 months, death-censored graft failure, all-cause and cardiovascular mortality, and a composite of graft failure and mortality. RESULTS: A total of 4935 HD patients (378 extended hour HD, 4557 conventional HD) received a kidney transplant during the study period. Extended hour HD was associated with an increased likelihood of DGF compared with conventional HD (adjusted proportional odds ratio 1.33; 95% confidence interval 1.06-1.67). There was no significant difference between extended hour and conventional HD in terms of any of the secondary outcomes. CONCLUSION: Compared to conventional HD, extended hour HD was associated with DGF, although long-term graft and patient outcomes were not different.

Successful heart-kidney transplantation from a Hepatitis C viremic donor to negative recipient: One year of follow-up.

Every year the number of patients waiting for a heart transplant increases faster than the number of available donor organs. Some potential donor organs are from donors with active communicable diseases, including hepatitis C virus (HCV), potentially making donation prohibitive. The advent of direct-acting antiviral agents for HCV has drastically changed the treatment of HCV. Recently, these agents have been used to treat HCV in organ donor recipients who acquired the disease from the donor organ. We report a case of heart-kidney transplantation from an HCV viremic donor to HCV negative recipient with successful treatment and sustained virologic response.